The use of recombinant vaccinia viruses expressing foreign proteins as a live vaccine is a promising field of investigation. Because of adverse events that occurred during the smallpox eradication program, a safer vaccinia virus vaccine vector needs to be developed before it can be widely used. By studying the various proteins that the virus uses to evade the host immune response, a safe and effective vaccine vector can be designed. A group of viral defense molecules that require further study are the vaccinia virus proteins related to the super-family of mammalian complement control proteins. We propose to investigate the structural and functional characteristics of the viral proteins' interactions with complement in vitro in order to better understand the mechanism by which vaccinia virus modulates complement activation. Furthermore, we will compare the complement regulatory activity of the vaccinia virus proteins with that of known regulators of complement activation. The second aim of this proposal will be to study the role of the viral proteins in vaccinia virus pathogenesis using an animal model of infection. The histopathology of the lesions formed by wild type vaccinia virus and a mutant virus that does not express the complement binding protein will be investigated. Additionally, the viral titers present in these lesions will be studied. The examination of viral proteins that interact with the host immune system will lead to a better comprehension of the host defenses against viral infections. The logical and judicious manipulation of the vaccinia virus genome will allow the construction of a safe and effective vaccine vector. Additionally, the study of the viral proteins involved in regulating complement may lead to the rational design of chemotherapeutic agents that might be able to control disease processes induced by an overly zealous complement activation.